The symptom most commonly experienced with patients with traumatic brain injury combined with and stress is recurrent post-traumatic headache (PTH). While 35-60% of patients with mild TBI experience headache, in combination with an intense stressor, the rate of headache in this patient population rises to 85%. PTH shares many features with migraine, including facial allodynia, aura, and sensitivity to sensory stimuli, suggesting that these two conditions may develop through overlapping mechanisms. A growing body of evidence now implicates that migraine, and potentially PTH, may arise from the dura that leads to activation/sensitization of dural afferent neurons. While we have previously demonstrated the effect of stress alone on dural afferent excitability and dural immune cell density, it is likely that TBI with stress potentiates these events, shifting the dural environment from inhibitory to excitatory to drive PTH, if not migraine. Therefore, this proposal will employ a clinically ? relevant animal model to determine if immune molecules and adrenergic receptors are involved in the potentiation of PTH that results from TBI and stress. First, I will test headache-linked behaviors, facial tactile allodynia and grimacing, paired with in vivo recordings of spontaneous and evoked calcium transients in dural afferents in animals with TBI with stress. Second, I will assess if dural afferent excitability is altered in animals with TBI and stress. Finally, I will measure the density and phenotype of dural immune cells and the cytokines they express in animals with TBI and stress. Results from these experiments will provide information in which dural afferents and the milieu of dural immune cells contribute to the maintenance of PTH. In the proposed experiments, I will employ an array of behavioral assays and in vivo microscopy paired with patch clamp electrophysiology and flow cytometry and cytokine expression. Thus, the successful completion of the proposed experiments will provide novel information regarding the function of a protein critical for Ca2+ regulation, suggest novel therapeutic approaches for the treatment of inflammatory pain, and provide a solid experimental foundation upon which to build a career as an independent scientist.